Epigenetic Disordering Drives Stemness, Senescence Escape and Tumor Heterogeneity [scRNAseq_hUHRF1]

We show that high levels of the epigenetic regulator and oncogene, UHRF1, in zebrafish hepatocytes rapidly induced methylome disordering, loss of heterochromatin, and DNA damage, resulting in cell cycle arrest, senescence, and acquisition of stemness.

Reducing UHRF1 expression transitions these cells from senescent to proliferation-competent. The expansion of these damaged cells results in hepatocellular carcinomas (HCC) that have immature cancer cells intermingled with fibroblasts, immune and senescent cells expressing high UHRF1 levels, which serve as reservoirs for new cancer cells. Here, we performed scRNAseq in zebrafish livers with UHRF1 overexpressing hepatocytes and controls, in which membrane ocalized EGFP was expressed, at time points in which we observe senescence, senescence escape and HCC formation.